We originally showed that mice that inherit a Gnas exon 2 insertion paternally are leaner than normal and are hypermetabolic and hyperactive, while mice which inherit the mutation maternally become obese, hypometabolic, and hypoactive. Detailed metabolic studies have shown the paternal exon 2 knockout mice to have increased adiponectin and resistin expression in adipose tissue, increased whole body lipid metabolism, and increased insulin sensitivity in adipose tissue, muscle, and liver. We have created a new mouse line with flox sites around Gs-alpha exon 1, and with this have made mice with Gs-alpha specific deficiency. Heterozygous Gs-alpha-deficient mice develop obesity and insulin resistance, with the phenotype being more severe in maternal mice. These differences are presumably due to Gs-alpha imprinting, and this is supported by preliminary evidence that the paternal exon 1A deletion, which is known to be required for paternal Gs-alpha imprinting, can reverse the obesity resulting from maternal Gs-alpha deficiency. We are presently doing heterozygous tissue-specific Gs-alpha knockouts to determine the tissue in which Gs-alpha deficiency leads to obesity. Recent studies show a similar imprinting effect in humans, with pseudohypoparathyroidism type 1a patients developing greater obesity than pseudopseudohypoparathyroidism patients. We also showed that mice with XL-alpha-s deficiency are severely lean and insulin sensitive, with increased sympathetic nervous system activity. This isoform presumably is a negative regulator of sympathetic nervous system activity, and XL-alpha-s deficiency is the cause of the paternal exon 2 deletion phenotype. We have also generated tissue-specific Gs-alpha knockouts in various metabolically active tissues. Liver-specific Gs-alpha deficiency leads to increased insulin sensitivity in multiple tissues, reduced adiposity, and maintenance of normal fasting blood sugars due to long-term breakdown of larger than normal glycogen stores. Studies in adipose-specific knockout mice show that Gs-alpha is required for normal adipogenesis and that two forms of adaptive thermogenesis (cold-induced and diet-induced) occur in different tissues. Studies in muscle-specific knockout mice suggest an important role in Gs-alpha (presumably beta adrenergic) pathways in glucose disposal by muscle. Also, studies in islet-beta cell-specific Gs-alpha deficient mice confirm an important role for these pathways in islet maintenance and insulin secretion, as the mice develop insulin-deficient diabetes.